1. Field of the Invention
The present invention relates to a drug delivery carrier and, more particularly, to a drug delivery carrier of a nanoparticle used for transporting target molecules to the cells expressed with somatostatin receptors.
2. Description of Related Art
Somatostatin is an endogenous regulator related to the endocrine system, whose relative molecule, a somatostatin receptor, is usually distributed in the endocrine systems or digestive organs of the healthy body. Recently, some studies have indicated that the somatostatin receptor is also over-expressed in the tumor cells of some cancer patients. The somatostatin receptor is found in small cell lung cancer (SCLC), ovarian cancer, breast cancer, lymphoma, leukemia, astrocytoma, meningioma, renal cancer, cancers in gut, central neural and neuroendocrine systems and is also reported clinically in hepatic cellular carcinoma and carcinoid cancer. Several somatostatin analogues were developed and, in general, used for radioactive imaging in medical diagnosis to locate the tumor in the cancer patients, or treatment with radiotherapy, see U.S. Pat. Nos. 6,358,491, 6,241,965, 5,871,711 and 5,814,298. Recently, a prodrug has been synthesized by chemically conjugating octreotide and related drugs for the target medication in a breast cancer cell (MCF-7), see U.S. Pat. No. 6,191,290. However, prodrug is rather smaller than liposomes or nanoparticle carriers which can provide enhanced accumulation in tumor site because of the designed particle size. In addition, lipsosomes or nanoparticle carriers also offer multi-ligands on the surface of the liposomes to bind with somatostatin receptors of the cells. The interaction will help liposomes or nanoparticle carriers to enter cell effectively. In another aspect, it is found that the somatostatin receptor is also expressed in the angiogenic vein vessels adjacent to some tumors. Researcher used somatostatin analogues to treat cancer by inhibition of angiogensis around tumors. Therefore, liposomes or other nanoparticles resulted from the conjugation of somatostatin (or somatostatin analogues) with lipids or (polymers) can target to the somatostatin receptor-expressed tumors or angiogenic vascular cells. Furthermore, due to the diversity and large capacity of liposomes and nanoparticles, they may carry genes or drugs and deliver them into specific cells through endocytosis for the desired therapy.
The particles used in the present administration system, such as liposomes or polymers, are in submicron level and cannot perform the selectivity or active targeting to specific cells. Therefore, it is required to develop a ligand for introducing nanoparticle administration system to selectively target the receptor-specific cells and thus improve the potency and further reduce side effects. At present, an antibody is used for this purpose, see U.S. Pat. Nos. 6,316,024, 6,300,319 and 6,004,534. However, the antibody is also involved in the immune response. That is, once the antibody is conjugated to the particle surface for the aforesaid purposes, an unpredictable immune response may occur inside the body. Another question is, due to the larger particle size of the aforesaid liposomes (or polymers) administration system, the particles introduced to the specific cell surface via the antibody may not enter the target cells via receptor-mediaetd endocytosis. Therefore, to develop somatostatin (or somatostatin analogue) as a ligand for introducing an administration system of nanoparticles in targeting a specific tumor or angiogenic vessel surface, for inducing endocytosis of the aforesaid cells, and for enhancing the drug or gene delivery, has become the immediate challenge.
The new generation of active targeting administration system utilizes a ligand that can recognize the target cells to selectively introduce a drug to these specific target cells. For example, an antibody [U.S. Pat. Nos. 6,316,024, 6,300,319 and 6,004,534], an antibody fragment [U.S. Pat. Nos. 6,056,973 and 6,043,094], a peptide [Cancer Res. 61:3978-85 (2001), BBA 1514(2):303-17 (2001) and J. Control Release 74:129-134 (2001)] or a small molecule compound is used as a ligand conjugated on the particle surface to assist liposomes to target the specific cells selectively. However, most of these ligands merely act on the specific cell surface and are not certain to induce the receptor-mediated endocytosis of the aforesaid specific cells, hence, the capacity for the system for delivering drugs into the cells may not reach the level anticipated and desired.
The somatostatin analogue can be regarded as a drug for gastrointestinal system cancer therapy, and moreover, it is also used for radioactive diagnosis and therapy. Most patent literatures related to somatostatin analogue focus on the treatment for gastrointestinal system cancer. Actually, many medical products of somatostatin analogue have already applied extensively in clinical therapy. In addition, a somatostatin analogue is chemically conjugated with paclitaxel to form a prodrug for the cancer target or for carrying a radionuclide for regional radiotherapy. However, the somatostatin analogue is yet to be taken as a ligand located on surface of liposomes or nanoparticles.
The vascular wall adjacent to the tumor is looser than the normal, so more nutrients are allowed to supplement. The vascular wall has a pore size around 200 nanometers (nm). Therefore, in the current study, for improving the circulating time in blood and for achieving the accumulation of the particles in the tumor, the liposome size is controlled in an order of around 100 nm and the hydrophobility of the liposome surface is modified. However, in this situation, the range of the liposome size is largely restricted. The alternative is to change the target (e.g. vascular cells adjacent to tumors instead of vascular wall) of drug delivery in tumor treatment. If the vascular cells adjacent to the tumor is taken as an object for target therapy, the particle size range can be enlarged the threshold size of actual endocytosis.